In 2009, a genetically enhanced, 9-year-old female super-soldier who calls herself Max Guevara (Jessica Alba), escapes along with eleven others like herself from a secret government institution, codenamed Manticore, where they were born, raised and trained to be soldiers and assassins. On June 1, 2009, months after Max's escape, terrorists detonate an electromagnetic pulse weapon inthe atmosphere over the U.S., which destroys the vast majority of computer and communication systems, throwing the country into utter chaos.
The first season begins ten years later in 2019, as it follows the life of the now 19-year-old Max as she struggles to search for herManticore brothers and sisters. In a United States which is now barely more than a Third World nation, she tries to live her life, evade capture, and learn to trust and love. She becomes involved with Logan Cale (Michael Weatherly), an underground cyber-journalist with the alias Eyes Only, who recruits her to help fight corruption in the post-Pulse world, while at the same time she makes a living as a bicycle messenger at a courier company named Jam Pony along with her friends Original Cindy (Valarie Rae Miller), Herbal Thought (Alimi Ballard), and Sketchy (Richard Gunn). Other X-5s are periodically introduced, most significantly Zack(William Gregory Lee), the unit leader and eldest brother. The Manticore hunt for the escaped X-5s is led by Colonel Donald Lydecker (John Savage), who is ousted at the end of the season by the even more ruthless Elizabeth Renfro (Nana Visitor).
In the second season of the show, the tone changes as Max and Logan bring down Manticore and free all the transgenics within. Two others become main characters: Alec (Jensen Ackles), a fellow X-5 who joins Jam Pony, and Joshua (Kevin Durand), atransgenic with canine DNA. Max later learns that Joshua was the first transgenic created by Manticore's founder Sandeman. It becomes apparent that Manticore produced many different human/animal mixes as well as other experiments with unique abilities. A major theme in the second season is the discovery of an even more deadly enemy than Lydecker or Renfro, namely a millennia-old breeding cult similar in structure to theIlluminati. This has resulted in humans even more formidable than the Manticore-produced transgenics, and even some with strong telekinetic powers. Ames White (Martin Cummins), a government agent introduced early in the second season trying to eliminate the loose transgenics, is revealed to be a member of the cult. When a strange message written in Max's genetic code makes an appearance on her skin, it is revealed that Sandeman is a renegade from the breeding cult and Ames White is his son, who is still loyal to the cult and hates his father's transgenic creations with a passion. The second season ends before Sandeman's plan for Max can be revealed.